The present invention relates to novel compounds, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.
Chemokines play an important role in immune and inflammatory responses in various diseases and disorders, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. These small secreted molecules are a growing superfamily of 8-14 kDa proteins characterised by a conserved four cysteine motif. The chemokine superfamily can be divided into two main groups exhibiting characteristic structural motifs, the Cys-X-Cys (C-X-C) and Cys-Cys (C-C) families. These are distinguished on the basis of a single amino acid insertion between the NH-proximal pair of cysteine residues and sequence similarity.
The C-X-C chemokines include several potent chemoattractants and activators of neutrophils such as interleukin-8 (IL-8) and neutrophil-activating peptide 2 (NAP-2).
The C-C chemokines include potent chemoattractants of monocytes and lymphocytes but not neutrophils such as human monocyte chemotactic proteins 1-3 (MCP-1, MCP-2 and MCP-3), RANTES (Regulated on Activation, Normal T Expressed and Secreted), eotaxin and the macrophage inflammatory proteins 1xcex1 and 1xcex2 (MIP-1 xcex1 and MIP-1xcex2).
Studies have demonstrated that the actions of the chemokines are mediated by subfamilies of G protein-coupled receptors, among which are the receptors designated CCR 1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3 and CXCR4. These receptors represent good targets for drug development since agents which modulate these receptors would be useful in the treatment of disorders and diseases such as those mentioned above.
Certain piperidinyl derivatives and piperazinyl derivatives are known from U.S. Pat. Nos. 3,787,419, 4,559,349 and 5,210,086 for use respectively as central nervous system depressants, antipsychotic agents and as xcex11-adrenoreceptor antagonists.
In accordance with the present invention, there is therefore provided a compound of general formula 
wherein:
R1 represents a C1-C12 alkyl group optionally substituted by one or more substituents independently selected from cyano, hydroxyl, C1-C6 alkoxy, C1-C6 alkylthio and C1-C6 alkoxycarbonyl groups, or
R1 represents a 3- to 10-membered saturated or unsaturated ring system which may comprise up to two ring carbon atoms that form carbonyl groups and which may comprise up to 4 ring heteroatoms independently selected from nitrogen, oxygen and sulfur, the ring system being optionally substituted by one or more substituents independently selected from halogen atoms, and cyano, nitro, hydroxyl, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, xe2x80x94NR5R6, C3-C6 cycloalkylamino, C1-C6 alkylthio, C1-C6 alkylthioC1-C6 alkyl, C1-C6 alkylcarbonylamino, xe2x80x94C(O)NR7R8, sulphonamido (xe2x80x94SO2NH2), (di)C1-C6 alkylsulphonamido, phenyl, phenylamino, nitrophenyl, pyridyl, pyridylthio, benzodioxanyl, thienyl, furanyl, and C(O)R9-substituted C1-C6 alkyl or C1-C6 alkoxy groups;
M is 0 or 1;
Q represents a group OCH2, C1-C4 alkylene or C2-C4 alkenylene;
T represents a group C(O)NH, or when m is 0, T may additionally represent a bond or a group NH, or when m is 1 and Q represents C1-C4 alkylene, T may additionally represent a group NH;
n is 1, 2, 3 or 4;
each R2 independently represents a hydrogen atom or a C1-C4 alkyl group;
each R3 independently represents a hydrogen atom or a C1-C4 alkyl group;
V represents a nitrogen atom;
W represents a nitrogen atom or a group CH;
X represents an oxygen atom or a group C(O), CH(OH), NH or N(C1-C6 alkyl), provided that when W represents a nitrogen atom, then X represents C(O);
R4 represents a phenyl group optionally substituted by one or more substituents independently selected from halogen atoms, and amino, nitro, cyano, sulphonyl (xe2x80x94SO3H), sulphonamido (xe2x80x94SO2NH2), C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy and C1-C6 alkylsulphonyl groups;
R5 and R6 each independently represent a hydrogen atom or a C1-C6 alkyl or hydroxyC1-C6 alkyl group, or R5 and R6 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;
R7 and R8 each independently represent a hydrogen atom or a C1-C6 alkyl group; and
R9 represents a hydroxyl or xe2x80x94NR7R8 group;
with the provisos that
(a) when m is 0, T is CONH, n is 2, 3 or 4 and each R2 and R3 represents hydrogen, W is CH, X is C(O) or CH(OH) and R1 represents a substituted 3- to 10-membered unsaturated ring system, then the one or more substituents in the ring system do not include hydroxyl, halogen, C1-C6 alkoxy or C1-C6 haloalkoxy, and
(b) when W is N, X is C(O), R4 represents 3-trifluoromethylphenyl, m is 0 and T is a bond, then R1 and (CR2R3)n taken together do not represent a C1-C6 alkyl group, and
(c) when W is CH, X is O, n is 2 or 3 and each R2 and R3 represents hydrogen, m is 0 and T is NH, then R1 does not represent a group 
or a pharmaceutically acceptable salt or solvate thereof.
In the context of the present specification, an alkyl substituent group or an alkyl moiety in a substituent group may be linear or branched. Further, the alkyl moieties in a dialkylamino, di(hydroxyalkyl)amino or dialkylsulphonamido substituent group may be the same or different.
R1 represents a C1-C12, preferably C1-C10, alkyl group optionally substituted by one or more (e.g. one, two, three or four) substituents independently selected from cyano, hydroxyl, C1-C6, preferably C1-C4, alkoxy (e.g. methoxy, ethoxy, propoxy, butoxy, pentoxy or hexoxy), C1-C6, preferably C1-C4, alkylthio (e.g. methyl-, ethyl-, propyl-, butyl-, pentyl- or hexylthio) and C1-C6, preferably C1-C4, alkoxycarbonyl (e.g. methoxy-, ethoxy-, propoxy-, butoxy-, pentoxy- or hexoxycarbonyl) groups, or R1 represents a 3- to 10-membered saturated or unsaturated ring system comprising up to two ring carbon atoms that form carbonyl groups and comprising up to 4 ring heteroatoms independently selected from nitrogen, oxygen and sulfur, the ring system being optionally substituted by one or more (e.g. one, two, three or four) substituents independently selected from halogen atoms (fluorine, chlorine, bromine or iodine), and cyano, nitro, hydroxyl, C1-C6 alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl or hexyl), C3-C6 cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), C1-C6 alkoxy (e.g. methoxy, ethoxy, propoxy, butoxy, pentoxy or hexoxy), C1-C6 alkoxycarbonyl (e.g. methoxy-, ethoxy-, propoxy-, butoxy-, pentoxy- or hexoxycarbonyl), C1-C6 haloalkyl (e.g. trifluoromethyl), C1-C6 haloalkoxy (e.g. trifluoromethoxy), xe2x80x94NR5R6, C3-C6 cycloalkylamino (cyclopropyl-, cyclobutyl-, cyclopentyl- or cyclohexylamino), C1-C6 alkylthio (e.g. methyl-, ethyl-, propyl-, butyl-, pentyl- or hexylthio), C1-C6 alkylthioC1-C6 alkyl (e.g. methylthiomethyl), C1-C6 alkylcarbonylamino (e.g. methyl-, ethyl-, propyl-, butyl-, pentyl- or hexylcarbonylamino), xe2x80x94C(O)NR7R8, sulphonamido (xe2x80x94SO2NH2), (di)C1-C6 alkylsulphonamido (e.g. (di)methylsulphonamido or (di)ethylsulphonamido), phenyl, phenylamino, nitrophenyl, pyridyl, pyridylthio, benzodioxanyl, thienyl, furanyl, and C(O)R9-substituted C1-C6 alkyl or C1-C6 alkoxy groups, the alkyl and alkoxy moieties being as defined above.
The 3- to 10-membered saturated or unsaturated ring system in the group R1 may be monocyclic, or polycyclic comprising 2 or more fused rings, examples of which include cyclobutyl, cyclopentyl, cyclohexyl, norbornylenyl, adamantyl, piperidyl, phenyl, naphthyl, naphthyridinyl, 1,3-benzodioxolyl, pyrazolyl, furanyl, pyridyl, thienyl, benzoxazolyl, benzothiazolyl, chromonyl, imidazolyl, quinolinyl, isoquinolinyl, benzimidazolyl, pyrimidinyl, pyrazolopyrimidinyl, thienopyrimidinyl, thiazolopyrimidinyl, pyrimidinedione, pyrazinyl, pyridazinyl, purinyl, quinoxalinyl, thiazolyl, isothiazolyl and 2,4-dioxo-3,4-dihydro-quinazolinyl.
Preferably, R1 represents a C1-C10 alkyl group optionally substituted by one or two substituents independently selected from cyano, hydroxyl, C1-C4 alkoxy, C1-C4 alkylthio and C1-C4 alkoxycarbonyl groups, or R1 represents a 3- to 10-membered saturated or unsaturated ring system comprising up to two ring carbon atoms that form carbonyl groups and comprising up to 4 ring heteroatoms independently selected from nitrogen, oxygen and sulfur, the ring system being optionally substituted by one, two or three substituents independently selected from halogen atoms, and cyano, nitro, hydroxyl, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, C1-C3 haloalkyl, C1-C3 haloalkoxy, xe2x80x94NR5R6, C3-C6 cycloalkylamino, C1-C4 alkylthio, C1-C4 alkylthioC1-C4 alkyl, C1-C4 alkylcarbonylamino, xe2x80x94C(O)NR7R8, phenyl, phenylamino, nitrophenyl, pyridyl, pyridylthio, benzodioxanyl, thienyl, furanyl, and C(O)R9-substituted C1-C4 alkyl or C1-C4 alkoxy groups.
Preferably Q represents a group OCH2, C1-C3 alkylene or C2-C3 alkenylene.
Each R2 independently represents a hydrogen atom or a C1-C4 alkyl (e.g. methyl, ethyl, propyl, isopropyl or butyl) group, and is especially a hydrogen atom.
Each R3 independently represents a hydrogen atom or a C1-C4 alkyl (e.g. methyl, ethyl, propyl, isopropyl or butyl) group, and is especially a hydrogen atom.
Preferably n is 2 or 3.
X preferably represents an oxygen atom or a group C(O) or NH.
R4 represents a phenyl group optionally substituted by one or more (e.g. one, two, three or four) substituents independently selected from halogen atoms (fluorine, cholorine, bromine or iodine), and amino, nitro, cyano, sulphonyl (xe2x80x94SO3H), sulphonamido (xe2x80x94SO2NH2), C1-C6, preferably C1-C4, alkyl (e.g. methyl, ethyl, propyl, butyl, pentyl or hexyl), C1-C6, preferably C1-C4, haloalkyl (e.g. trifluoromethyl), C1-C6, preferably C1-C4, haloalkoxy (e.g. trifluoromethoxy) and C1-C6, preferably C1-C4, alkylsulphonyl (e.g. methyl-, ethyl-, propyl-, butyl-, pentyl- or hexylsulphonyl) groups.
Preferably, R4 represents a phenyl group optionally substituted by one or two halogen atoms, particularly chlorine atoms.
R5 and R6 each independently represent a hydrogen atom or a C1-C6, preferably C1-C4, alkyl or hydroxyC1-C6, preferably C1-C4, alkyl group, or R5 and R6together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring. The alkyl moiety in each case may, for example, be a methyl, ethyl, propyl, butyl, pentyl or hexyl group. In the hydroxyalkyl group, the hydroxyl group may be attached to any suitable carbon atom of the alkyl moiety.
R7 and R8 each independently represent a hydrogen atom or a C1-C6, preferably C1-C4, alkyl (e.g. methyl, ethyl, propyl, butyl, pentyl or hexyl) group. Preferably, R7 and R8 each independently represent a hydrogen atom or a methyl group.
R9 represents a hydroxyl or, preferably, xe2x80x94NR5R6 group.
Examples of particularly preferred compounds of the invention include:
4-Chloro-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}-2-[2-(dimethylamino-2-oxoethoxy]benzamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-3-ethoxybenzamide hydrochloride,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4-isopropoxybenzamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4-ethoxybenzamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-3-(trifluoromethoxy)benzamide hydrochloride,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4-methoxybenzamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4-(trifluoromethoxy)benzamide hydrochloride,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-furamide hydrochloride,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-phenylacetamide hydrochloride,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-3-methoxybenzamide hydrochloride,
3-Chloro-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}benzamide hydrochloride,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4-fluorobenzamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-3-fluorobenzamide hydrochloride,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-3-hydroxybenzamide hydrochloride,
N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-3-[2-(methylamino)-2-oxoethoxy]benzamide hydrochloride,
2-[3-{2-[4-(4-Fluorobenzoyl)-1-piperidinyl]ethyl}-2,4-dioxo-3,4-dihydro-1(2H) -quinazolinyl]-N,N-dimethylacetamide hydrochloride,
N-{2-[4-(3,4-Dichlorobenzoyl)-1-piperazinyl]ethyl}-3-methoxybenzamide hydrochloride,
3,4-Dichloro-N-{2-[4-(3,4-dichlorobenzoyl)-1-piperazinyl]ethyl}benzamide,
4-Chloro-N-{2-[4-(3,4-dichlorobenzoyl)-1-piperazinyl]ethyl}-2-[2-(dimethylamino)-2-oxoethoxy]benzamide hydrochloride,
Nxcx9c7xcx9c-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-5-methyl[1,3]thiazolo[4,5-d]pyrimidine-2,7-diamine,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-9-methyl-9H-purin-6-amine,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-1,3-benzothiazol-2-amine,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-1,3-benzoxazol-2-amine,
6-Chloro-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}-2-pyrazinamine,
6-Chloro-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}-3-pyridazinamine,
6-({2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}amino)-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione,
N-{1-[4-(3,4-Dichlorophenoxy)-piperidinyl-1-ylmethyl]-2-methyl-propyl}4-methyl-benzamide, hydrochloride salt,
N-{1-[4-(3,4-Dichloro-phenoxy)-piperidinyl-1-ylmethyl]-2-methyl-propyl}-3-methoxy-benzamide, hydrochloride salt,
N-{2-[4-(3,4-Dichloroanilino)-1-piperidinyl]ethyl}-3-methoxybenzamide dihydrochloride,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-N-(3-methoxybenzyl)amine dihydrochloride,
3-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-6-methoxy-2,4(1H,3H)-quinazolinedione,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl ) -3-fluorobenzamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl benzamide,
4-Chloro-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}benzamide,
N-{2-2[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}4-methoxybenzamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-methoxybenzamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-3-methoxybenzamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-nitrobenzamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-methylbenzamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-3-(trifluoromethyl)benzamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-3,5-dinitrobenzamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-inodobenzamide,
4-Cyano-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}benzamide,
4-Bromo-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}benzamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}4-methylbenzamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4-nitrobenzamide,
3-Bromo-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}benzamide,
3,4-Dichloro-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}benzamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4-fluorobenzamide,
2,4-Dichloro-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}benzamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-3-methylbenzamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4-iodobenzamide,
4-Chloro-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}-3-nitrobenzamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4-methyl-3-nitrobenzamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-fluoro-5-(trifluoromethyl)benzamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-3-(trifluoromethoxy)benzamide,
3,5-Dichloro-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}benzamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4-(trifluoromethyl)benzamide,
3-Cyano-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}benzamide,
2-Bromo-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}-5-methoxybenzamide,
N-2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-furamide,
3-Chloro-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}benzamide,
2-Chloro-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}benzamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}1-3,5-difluorobenzamiide,
2,3-Dichloro-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}benzamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-naphthamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-(methylsulfanyl)nicotinamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-fluoro-6-(trifluoromethyl)benzamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2,4-difluorobenzamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-thiophenecarboxamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-quinoxalinecarboxamide,
Methyl 4-({2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}amino)-4-oxobutanoate,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}bicyclo[2.2.1]hept-5-ene-2-carboxamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}cyclobutanecarboxamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-methoxyacetamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}cyclohexanecarboxamide,
(E)-N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-3-phenyl-2-propenamide,
2-Chloro-N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}nicotinamide,
N-(2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-phenylacetamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-cyclopentanecarboxamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-phenoxyacetamide,
N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}benzamide,
N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-3-(trifluoromethyl)benzamide,
4-(tert-Butyl)-N-{2-[4-(4-chlorobenzoyl)-1-piperidinyl]ethyl}benzamide,
N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-4-methylbenzamide,
N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-4-nitrobenzamide,
N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-3-methylbenzamide,
N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-4-methyl-3-nitrobenzamide,
N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-3-cyanobenzamide,
N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-2-furamide,
N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-3- nitrobenzamide,
N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-2-naphthamide,
N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-2-(methylsulfanyl)nicotinamide,
N-{2[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-2-(2,3-dihydro-1,4-benzodioxin-2-yl)-1,3-thiazole4-carboxamide,
Nxcx9c2xcx9c-Cyclopropyl-Nxcx9c4xcx9c-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}-2,4-pyrimidinediamine,
2-{[4-({2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}amino)-2-pyrimidinyl]amino }-1-ethanol,
2-[[4-({2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}amino)-2-pyrimidinyl](methyl)amino]-1-ethanol,
Nxcx9c4xcx9c-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-Nxcx9c2xcx9c-phenyl-2,4-pyrimidinediamine,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-(methylsulfanyl)-4-pyrimidinamine,
Nxcx9c4xcx9c-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-6-methyl-2,4-pyrimidinediamine,
Nxcx9c4xcx9c-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-Nxcx9c2xcx9c,6-dimethyl-2,4-pyrimidinediamine,
2-Chloro-Nxcx9c4xcx9c-cyclopropyl-Nxcx9c6xcx9c-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}-4,6-pyrimidinediamine,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4-phenyl-2-pyrimidinamine,
Nxcx9c2xcx9c-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-Nxcx9c4xcx9c,Nxcx9c4 xcx9c, 6-trimethyl-2,4-pyrimidinediamine,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4-(trifluoromethyl)-2-pyrimidinamine,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4-(propylsulfanyl)-2-pyrimidinamine,
Nxcx9c2xcx9c-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-Nxcx9c4-phenyl-2,4-pyrimidinediamine,
Nxcx9c4xcx9c-Cyclopropyl-Nxcx9c2xcx9c-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}-2,4-pyrimidinediamine,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}[1,8]naphthyridin-2-amine,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4-(3-pyridinyl)-2-pyrimidinamine,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-pyrimidinamine,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4,6-dimethoxy-2-pyrimidinamine,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4-(3-furyl)-2-pyrimidinamine,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-1H-purin-6-amine,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-5-methylthieno[2,3-d]pyrimidin-4-amine,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-7-methylthieno[3,2-d]pyrimidin-4-amine,
N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-2-thiophenecarboxamide,
N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-2-quinoxalinecarboxamide,
N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}bicyclo[2.2.1]hept-5-ene-2-carboxamide,
N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}cyclohexanecarboxamide,
(E)-N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-3-phenyl-2-propenamide,
N-{2-[4(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-2-phenoxyacetamide,
(E)-N-{2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}-3-(4-nitrophenyl)-2-propenamide,
2-(1-Adamantyl)-N-{2-[4-(4-chlorobenzoyl)-1-piperidinyl]ethyl}acetamide,
(4-Chlorophenyl)(1-{2-[(2-fluoro-4,5-dimethoxybenzyl)amino]ethyl}4-piperidinyl)methanone,
(4-Chlorophenyl)(1-{2-[(3,4,5-trimethoxybenzyl)amino]ethyl)4-piperidinyl)methanone,
(4-Chlorophenyl)(1-{2-[(3-nitrobenzyl)amino]ethyl}-4-piperidinyl)methanone,
(4-Chlorophenyl){1-[2-(isobutylainino)ethyl]-4-piperidinyl}methanone,
4-[({2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}amino)methyl]-4-ethylhexanenitrile,
(4-Chlorophenyl)(1-{2-[(7-hydroxy-3,7-dimethyloctyl)amino]ethyl}-4-piperidinyl)methanone,
(4-Chlorophenyl)[1-(2-{[(6-nitro-1,3-benzodioxol-5-yl)methyl]amino}ethyl)4-piperidinyl]methanone,
[1-(2-{[(5-Chloro-1,3-dimethyl-1H-pyrazol4-yl)methyl]amino}ethyl)4-piperidinyl](4-chlorophenyl)methanone,
(4-Chlorophenyl)[1-(2-{[3-nitro-4-(2-pyridinylsulfanyl)benzyl]amino}ethyl)-4-piperidinyl]methanone,
(4-Chlorophenyl)[1-(2-{[(E)-3-(4-nitrophenyl)-2-propenyl]amino}ethyl)4-piperidinyl]methanone,
(4-Chlorophenyl){1-[2-({[5-(3-nitrophenyl)-2-furyl]methyl}amino)ethyl]-4-piperidinyl}methanone,
(4-Chlorophenyl)[1-(2-1 [5-nitro-2-(2-pyridinylsulfanyl)benzyl]amino}ethyl)-4-piperidinyl]methanone,
6-[({2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}amino)methyl]-2-(methylsulfanyl)nicotinonitrile,
{1-[2-({[5-Chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl}amino)ethyl]-4-piperidinyl}(4-chlorophenyl)methanone,
(4-Chlorophenyl)[1-(2-{[3-(methylsulfanyl)butyl]amino}ethyl)-4-piperidinyl]methanone,
(4-Chlorophenyl)[1-(2-{[(4-phenyl-4-piperidinyl)methyl]amino}ethyl)-4-piperidinyl]methanone,
(4-Chlorophenyl)[1-(2-{[(1-phenyl-1H-pyrazol-5-yl)methyl]amino}ethyl)-4-piperidinyl]methanone,
Ethyl 3-[({2-[4-(4-chlorobenzoyl)-1-piperidinyl]ethyl}-amino)methyl]cyclohexanecarboxylate,
N-{4-[({2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}amino)methyl]phenyl}acetamide,
(4-Chlorophenyl)(1-{-2-[(2,5-difluorobenzyl)amino]ethyl}-4-piperidinyl)methanone,
(4-Chlorophenyl)(1-{2-[(4-nitrobenzyl)amino]ethyl}-4-piperidinyl)methanone,
(4-Chlorophenyl)(1-{2-[(2,6-dichlorobenzyl)amino]ethyl}-4-piperidinyl)methanone,
(4-Chlorophenyl)(1-{2-[(2-pyridinylmethyl)amino]ethyl}-4-piperidinyl)methanone,
(4-Chlorophenyl)[1-(2-{[(3-methyl-2-thienyl)methyl]amino}ethyl)-4-piperidinyl]methanone,
(4-Chlorophenyl)(1-{2-[(3-hydroxy-4-methoxybenzyl)amino]ethyl}-4-piperidinyl)methanone,
3-[({2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}amino)methyl]-4H-chromen-4-one,
[1-(2-{[(5-Chloro-1,3-dimethyl-1H-pyrazol4-yl)methyl]amino)ethyl)-4-piperidinyl](4-chlorophenyl)methanone,
(4-Chlorophenyl)[1-(2-{[(2,6-dichloro-4-pyridinyl)methyl]amino}ethyl)4-piperidinyl]methanone,
(4-Chlorophenyl)[1-(2-{[(2-phenyl-1H-imidazol-4-yl)methyl]amino}ethyl)-4-piperidinyl]methanone,
(4-Chlorophenyl)[1-(2-{[(5-ethyl-2-thienyl)methyl]amino}ethyl)-4-piperidinyl]methanone,
(4-Chlorophenyl)[1-(2-{[(2-chloro-3-quinolinyl)methyl]amino}ethyl)-4-piperidinyl]methanone,
(4-Chlorophenyl)[1-(2-{[(6-methyl-2-pyridinyl)methyl]amino}ethyl)-4-piperidinyl]methanone,
(4-Chlorophenyl)(1-{2-[(3-quinolinylmethyl)amino]ethyl}-4-piperidinyl)methanone,
4-[({2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}amino)methyl]-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one,
(4-Chlorophenyl)(1-{2-[(4-pyridinylmethyl)amino]ethyl}-4-piperidinyl)methanone,
(4-Chlorophenyl)(1-{2-[(3-hydroxy-4-nitrobenzyl)amino]ethyl}-4-piperidinyl)methanone,
(4-Chlorophenyl)(1-{2-[(3,5-difluorobenzyl)amino]ethyl}-4-piperidinyl)methanone,
(1-{2-[(2-Chloro-6-fluorobenzyl)amino]ethyl}-4-piperidinyl)(4-chlorophenyl)methanone,
[1-(2-{[(4-Bromo-1H-pyrazol-3-yl)methyl]amino}ethyl)-4-piperidinyl](4-chlorophenyl)methanone,
3-[({2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}amino)methyl]-6,7-dimethyl-4H-chromen-4-one,
2-{2-[({2-[4-(4-Chlorobenzoyl)-1-piperidinyl]ethyl}amino)methyl]-4-nitrophenoxy}acetic acid,
(4-Chlorophenyl)[1-(2-{[(1-methyl-1H-benzimidazol-2-yl)methyl]amino}ethyl)-4-piperidinyl]methanone, (
4-Chlorophenyl)[1-(2-{[(2,4-dimethoxy-5-pyrimidinyl)methyl]amino}ethyl)4-piperidinyl]methanone,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4-(methylamino)benzamide,
4-Chloro-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}-3-methoxybenzamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-3-methoxy-4-methylbenzamide,
3-Amino-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}4methoxybenzamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-1,3-benzodioxole-5-carboxamide,
4-Amino-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}-3-methoxybenzamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-3-fluoro-4-methoxybenzamide,
5-Bromo-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}-2-furamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-3-methyl-2-furamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4,5-dimethyl-2-furamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-7-ethoxy-1-benzofuran-2-carboxamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-5-methoxy-1-benzofuran-2-carboxamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-7-methoxy-1-benzofuran-2-carboxamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-(4-fluorophenyl)acetamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-(2-methoxyphenyl)acetamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-(3-methylphenyl)acetamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-(2-methylphenyl)acetamide,
2-(3-Bromophenyl)-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}acetamide,
2-(2-Chlorophenyl)-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}acetamide,
2-(4-Chlorophenyl)-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}acetamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-[2-(trifluoromethyl)phenyl]acetamide,
2-(3-Chlorophenyl)-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}acetamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-(3,4-dimethoxyphenyl)acetamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-(4-methoxyphenyl)acetamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-(3,4-dichlorophenyl)acetamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-(3-fluoro-4-methoxyphenyl)acetamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-(4-ethoxyphenyl)acetamide,
2-(1,3-Benzodioxol-5-yl)-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}acetamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-[4-(dimethylamino)phenyl]acetamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-(4-methylphenyl)acetamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-(3,4-difluorophenyl)acetamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-(3-methoxyphenyl)acetamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-4-phenylbutanamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-3-phenylpropanamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-3-(3-methoxyphenyl)propanamide,
2-Amino-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}-1,3-thiazole4-carboxamide,
2-(Acetylamino)-N-{2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]ethyl}-1,3-thiazole-4-carboxamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-(4-pyridinyl)-1,3-thiazole-4-carboxamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2,4-dimethyl-1,3-thiazole-5-carboxamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2,5-dimethyl-1,3-oxazole4-carboxamide,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-1H-imidazole-4-carboxamide,
N-{2-[4-(3,4-Chlorophenoxy)-1-piperidinyl]ethyl}-3-methoxybenzamide, hydrochloride salt,
N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine,
N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-2,6-dimethoxy-4pyrimidinamine,
Nxcx9c4xcx9c-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-Nxcx9c2xcx9c,Nxcx9c2xcx9c-dimethyl-2,4-pyrimidinediamine,
N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-2-[(methylsulfanyl)methyl]-4-pyrimidinamine,
N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-2-(methylsulfanyl)-6-(trifluoromethyl)-4-pyrimidinamine,
N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-5-methoxy-2-(methylsulfanyl)-4-pyrimidinamine,
N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-6-methyl-2-(methylsulfanyl)4-pyrimidinamine,
N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-5-methoxy-2-methyl-4-pyrimidinamine,
N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-2-(ethylsulfanyl)-6-methyl-4-pyrimidinamine,
Nxcx9c2xcx9c-Cyclopropyl-Nxcx9c4xcx9c-{3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]propyl}-2,4-pyrimidinediamine,
2-{[4-({3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}amino)-2-pyrimidinyl]amino}-1-ethanol,
2-[[4-({3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}amino)-2-pyrimidinyl](methyl)amino]-1-ethanol,
N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-2-(methylsulfanyl)-4-pyrimidinamine,
Nxcx9c4xcx9c-3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-6-methyl-2,4-pyrimidinediamine,
Nxcx9c4xcx9c-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-Nxcx9c2xcx9c,6-dimethyl-2,4-pyrimidinediamine,
N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-4-phenyl-2-pyrimidinamine,
Nxcx9c2xcx9c-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-5-fluoro-2,4-pyrimidineamine,
Nxcx9c2xcx9c-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-Nxcx9c4xcx9c,Nxcx9c4xcx9c, 6-trimethyl-2,4-pyrimidinediamine,
N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-4-(trifluoromethyl)-2-pyrimidinamine,
N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-4-(propylsulfanyl)-2-pyrimidinamine,
Nxcx9c2xcx9c-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-Nxcx9c4xcx9c-phenyl-2,4-pyrimidinediamine,
Nxcx9c2xcx9c-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-Nxcx9c4xcx9c,6-dimethyl-2,4-pyrimidinediamine,
N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}[1,8]naphthyridin-2-amine,
2-{[2-({3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}amino)-4-pyrimidinyl]amino}-1-ethanol,
2-[[2-({3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}amino)-4-pyrimidinyl](methyl)amino]-1-ethanol,
N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-4-(3-pyridinyl)-2-pyrimidinamine,
N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-4-(3-thienyl)-2-pyrimidinamine,
N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-2-pyrimidinamine,
N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-4,6-dimethoxy-2-pyrimidinamine,
N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-4-(3-furyl)-2-pyrimidinamine,
N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-4-(2-thienyl)-2-pyrimidinamine,
N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-1H-purin-6-amine,
N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-5-methylthieno[2,3-d]pyrimidin-4-amine,
N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-7-methylthieno[3,2-d]pyrimidin-4-amine,
Nxcx9c7xcx9c-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-5-methyl[1,3]thiazol[4,5-d]pyrimidine-2,7-diamine,
N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-9-methyl-9H-purin-6-amine,
N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-2-pyridinamine,
5-Chloro-N-{3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]propyl}-2-pyridinamine,
6-Chloro-N-{3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]propyl}-2-pyridinamine,
N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-6-methyl-2-pyridinamine,
N-{3-[4-(3,4-Dichlorophenoxy)- -piperidinyl]propyl}-1,3-benzothiazol-2-amine,
N-{3-[4-(3,4-Dichlorophenoxy)1-piperidinyl]propyl)}-1,3-benzoxazol-2-amine,
6-Chloro-N-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}-2-pyrazinamine,
6-Chloro-N-{3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]propyl}-3-pyridazinamine,
6-({3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]propyl}amino)-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2,6-dimethoxy-4-pyrimidinamine,
Nxcx9c4xcx9c-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-Nxcx9c2xcx9c,Nxcx9c2xcx9c, -dimethyl-2,4-pyrimidinediaoine,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-2-[(methylsulfanyl)methyl]-4-pyrimidinamine,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-5-methoxy-2-(methylsulfanyl)-4-pyrimidinamine,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-6-methyl-2-(methylsulfanyl)-4-pyrimidinamine,
N-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-5-methoxy-2-methyl-4-pyrimidinamine, and
Nxcx9c4xcx9c-{2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]ethyl}-6-methyl-Nxcx9c2xcx9c-phenyl-2,4-pyrimidinediamine.
The present invention further provides a process for the preparation of a compound of formula (I) which comprises
(i) when T represents a group C(O)NH, reacting a compound of general formula
R1xe2x80x94(Q)mxe2x80x94COL1xe2x80x83xe2x80x83(II)
wherein L1 represents a leaving group (e.g. a hydroxyl or halide, such as chloride, group) and R1, m and Q are as defined in formula (I), with a compound of general formula 
xe2x80x83or an acid addition salt thereof (e.g. trifluoroacetate) wherein n, R2, R3, V, W, X and R4 are as defined in formula (I); or
(ii) when T represents a group C(O)NH and W represents a nitrogen atom, reacting a compound of general formula 
wherein R1, m, Q, T, n, R2, R3 and V are as defined in formula (I), with a compound of general formula
L2xe2x80x94Xxe2x80x94R4xe2x80x83xe2x80x83(V)
wherein L2 represents a leaving group (e.g. a halogen atom) and X and R4 are as defined in formula (I); or
(iii) when T represents a group NH and m is 0, reacting a compound of general formula
R1xe2x80x94L3xe2x80x83xe2x80x83(VI)
wherein L3 represents a leaving group (e.g. a halogen atom) and R1 is as defined in formula (I), with a compound of formula (IH) as defined in (i) above; or
(iv) when T represents a group NH, m is 1 and Q represents C1-C4 alkylene, reacting a compound of general formula
R1xe2x80x94(CH2)pxe2x80x94CHOxe2x80x83xe2x80x83(VII)
wherein p is 0, 1, 2 or 3 and R1 is as defined in formula (I), with a compound of formula (III) as defined in (i) above; or
(v) when T represents a bond and m is 0, reacting a compound of general formula
R1xe2x80x94(CR2R3)nxe2x80x94L4xe2x80x83xe2x80x83(VIII)
wherein L4 represents a leaving group such as a halogen atom (e.g. chlorine) and n, R1, R2 and R3 are as defined in formula (I), with a compound of general formula 
wherein W, X and R4 are as defined in formula (I);
and optionally after (i), (ii), (iii), (iv) or (v) converting the compound of formula (I) to a further compound of formula (I) and/or forming a pharmaceutically acceptable salt or solvate of the compound of formula (I).
The processes of the invention may conveniently be carried out in a solvent, e.g. an organic solvent such as dimethylformamide or dichloromethane at a temperature of, for example, 15xc2x0 C. or above such as a temperature in the range from 20 to 100xc2x0 C.
Compounds of formula (III) in which W represents a nitrogen atom may be prepared by reacting a compound of general formula 
in which n, R2, R3and V are as defined in formula (I) with a compound of formula (V) as defined above.
Compounds of formula (X) can be prepared by reacting piperazine with a compound of general formula
H2Nxe2x80x94(CR2R3)nxe2x80x94L5xe2x80x83xe2x80x83(XI)
wherein L5 represents a halogen atom such as a bromine atom and n, R2 and R3 are as defined in formula (I).
Compounds of formula (III) in which W represents a group CH and X represents an oxygen atom may be prepared by reacting a compound of general formula 
in which R4 is as defined in formula (I), with a compound of formula (XI).
Compounds of formula (XII) may be prepared by reacting 4-piperidinol with a compound of general formula (XIII), R4xe2x80x94OH, wherein R4 is as defined in formula (I), in the presence of a coupling agent such as diethyl azodicarboxylate and triphenylphosphine and in a solvent such as benzene or tetrahydrofuran at a temperature typically in the range from 20 to 30xc2x0 C.
Compounds of formula (III) in which W represents a group CH and X represents a group C(O) may be prepared by reacting a compound of general formula 
wherein R4 is as defined in formula (I), with a compound of formula (XI).
Compounds of formula (III) in which W represents a group CH and X represents a group CH(OH) may be prepared by reducing/hydrogenating a corresponding compound of formula (III) in which X represents C(O) using techniques known in the art.
Compounds of formula (III) in which W represents a group CH and X represents a group NH may be prepared by reacting a compound of general formula 
in which R4 is as defined in formula (I), with a compound of formula (XI).
Compounds of formula (XV) may be prepared by reacting 4-piperidone with a compound of general formula (XVI), R4xe2x80x94NH2, wherein R4 is as defined in formula (I), in the presence of a reducing agent such as sodium cyanoborohydride or sodium borohydride and in a solvent such as methanol or benzene at a temperature typically in the range from 20 to 90xc2x0 C.
Compounds of formula (III) in which W represents a group CH and X represents a group N(C1-C6 alkyl) may be prepared by alkylating a corresponding compound of formula (III) in which X represents a group NH, using techniques conventional in the art.
Compounds of formula (IV) may be prepared by reacting a compound of formula (II) with a compound of formula (X).
Compounds of formulae II, V, VI, VII, VIII, IX, XI, XIII, XIV and XVI are either commercially available, are well known in the literature or may be prepared easily using known techniques.
Compounds of formula (I) can be converted into further compounds of formula (I) using standard procedures. For example, compounds of formula (I) in which R1 represents an alkoxy-substituted phenyl group can be converted to compounds of formula (I) in which R1 represents a hydroxy-substituted phenyl group by reaction with boron tribromide in a solvent such as dichloromethane. Further, compounds of formula (I) in which X represents C(O) can be converted to compounds of formula (I) in which X represents CH(OH) by reaction with triethylsilane and trifluoroacetic acid in a solvent such as dichloromethane.
It will be appreciated by those skilled in the art that in the processes of the present invention certain functional groups such as hydroxyl or amino groups in the starting reagents or intermediate compounds may need to be protected by protecting groups. Thus, the preparation of the compounds of formula (I) may involve, at an appropriate stage, the removal of one or more protecting groups.
The protection and deprotection of functional groups is described in xe2x80x98Protective Groups in Organic Chemistryxe2x80x99, edited by J. W. F. McOmie, Plenum Press (1973) and xe2x80x98Protective Groups in Organic Synthesisxe2x80x99, 2nd edition, T. W. Greene and P. G. M. Wuts, Wiley-Interscience (1991).
The compounds of formula (I) above may be converted to a pharmaceutically acceptable salt or solvate thereof, preferably an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate or p-toluenesulphonate.
Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses the use of all geometric and optical isomers of the compounds of formula (I) and mixtures thereof including racemates. The use of tautomers and mixtures thereof also form an aspect of the present invention.
The compounds of formula (I) have activity as pharmaceuticals, in particular as modulators of chemokine receptor (especially CCR1 and/or CCR3) activity, and may be used in the treatment of autoimmune, inflammatory, proliferative and hyperproliferative diseases and immunologically-mediated diseases including rejection of transplanted organs or tissues and Acquired Immunodeficiency Syndrome (AIDS).
Examples of these conditions are:
(1) (the respiratory tract) obstructive airways diseases including chronic obstructive pulmonary disease (COPD) such as irreversible COPD; asthma, such as bronchial, allergic, intrinsic, extrinsic and dust asthma, particularly chronic or inveterate asthma (e.g. late asthma and airways hyper-responsiveness); bronchitis; acute, allergic, atrophic rhinitis and chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca and rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous and pseudomembranous rhinitis and scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) and vasomotor rhinitis; sarcoidosis, farmer""s lung and related diseases, fibroid lung and idiopathic interstitial pneumonia;
(2) (bone and joints) rheumatoid arthritis, seronegative spondyloarthropathies (including ankylosing spondylitis, psoriatic arthritis and Reiter""s disease), Behcet""s disease, Sjogren""s syndrome and systemic sclerosis;
(3) (skin) psoriasis, atopical dermatitis, contact dermatitis and other eczmatous dermitides, seborrhoetic dermatitis, Lichen planus, Pemphigus, bullous Pemphigus, Epidermolysis bullosa, urticaria, angiodermas, vasculitides, erythemas, cutaneous eosinophilias, uveitis, Alopecia areata and vernal conjunctivitis;
(4) (gastrointestinal tract) Coeliac disease, proctitis, eosinopilic gastro-enteritis, mastocytosis, Crohn""s disease, ulcerative colitis, food-related allergies which have effects remote from the gut, e.g., migraine, rhinitis and eczema;
(5) (other tissues and systemic disease) multiple sclerosis, atherosclerosis, Acquired Immunodeficiency Syndrome (AIDS), lupus erythematosus, systemic lupus, erythematosus, Hashimoto""s thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, lepromatous leprosy, sezary syndrome and idiopathic thrombocytopenia pupura; and
(6) (allograft rejection) acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin and cornea; and chronic graft versus host disease.
Thus, the present invention provides a compound of formula (I), or a pharmaceutically-acceptable salt or solvate thereof, as hereinbefore defined for use in therapy.
In a further aspect, the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in the manufacture of a medicament for use in therapy.
In the context of the present specification, the term xe2x80x9ctherapyxe2x80x9d also includes xe2x80x9cprophylaxisxe2x80x9d unless there are specific indications to the contrary. The terms xe2x80x9ctherapeuticxe2x80x9d and xe2x80x9ctherapeuticallyxe2x80x9d should be construed accordingly.
The invention also provides a method of treating an inflammatory disease in a patient suffering from, or at risk of, said disease, which comprises administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined.
For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated.
The compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I) compound/salt/solvate (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99 % w (per cent by weight), more preferably from 0.05 to 80 % w, still more preferably from 0.10 to 70 % w, and even more preferably from 0.10 to 50 % w, of active ingredient, all percentages by weight being based on total composition.
The present invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
The invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined, with a pharmaceutically acceptable adjuvant, diluent or carrier.
The pharmaceutical compositions may be administered topically (e.g. to the lung and/or airways or to the skin) in the form of solutions, suspensions, heptafluoroalkane aerosols and dry powder formulations; or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules, or by parenteral administration in the form of solutions or suspensions, or by subcutaneous administration or by rectal administration in the form of suppositories or transdermally.